Mathematical Biology Seminar: Yue-Xian Li (UBC)

Reproduction in mammals is controlled by the pulsatile release of gonadotropin-releasing hormone (GnRH). About 800~2000 GnRH neurons participate in the generation of GnRH pulses. Their cell bodies are distributed in a scattered manner in designated areas of the hypothalamus. Although several experimental models including cultured hypothalamic tissues, placode-derived GnRH neurons, and GT1 cell lines have been developed and studied, a mechanistic explanation for the origin of GnRH pulsatility remains elusive. One major obstacle is identifying the mechanism for synchronizing scattered neurons. This talk is aimed at studying the viability of autocrine regulation in synchronizing GnRH neurons using mathematical models describing diffusely distributed GnRH neurons in two-dimensional space. The models discussed here are developed based on experiments in GT1 cells as well as hypothalamic neurons in culture. These experiments revealed that GnRH neurons express GnRH receptors that allow GnRH to regulate its own secretion through an autocrine effect. GnRH binding to its receptors on GnRH neurons triggers the activation of three types of G-proteins of which two activates and one inhibits GnRH secretion (Krsmanovic et al, 2003, PNAS 100:2969). These observations suggest GnRH secreted by GnRH neurons serve as a diffusive mediator as well as an autocrine regulator. A mathematical model has been developed (Khadra-Li, 2006, Biophys. J. 91:74) and its robustness and potential applicability to GnRH neurons in vivo investigated (Li-Khadra, 2008, BMB 70:2103). In this talk, I will introduce some key experimental and modeling results of this rhythm-generating system, focusing on the effects of intracellular distance, rate of hormone secretion, and spatial distribution on the ability of diffusely distributed GnRH neurons to synchronize through autocrine regulation. Based on the modeling results, one plausible explanation for why GnRH neurons are distributed in a scattered manner is proposed. (Results presented in here are based on works in collaboration with Anmar Khadra, Atsushi Yokoyama, and Patrick Fletcher.)